In mammals, and in humans in particular, cationic pharmaceuticals and xenobiotics of varying molecular structure, catecholamines and other endogenous cations are excreted in the kidney and liver by polyspecific transport proteins which are located in luminal and basolateral plasma membranes. These transport proteins differ, as regards their function, from the previously known monoamine transport proteins in neuronal plasma membranes and synaptic vesicles and from the ATP-dependent proteins for exporting hydrophobic pharmaceuticals (multidrug transport proteins).
Within the scope of the present invention, a complementary DNA sequence was initially isolated from rat kidneys, which sequence encodes a membrane protein of 556 amino acids in length and is designated OCT1 in that which follows. This transport protein acts in the basolateral membrane of the proximal renal tubules and in hepatocytes as a cation transporter for various target molecules.
The transport protein designated OCT1 is not homologous with any other previously known protein, exhibits a thus far unique distribution of hydrophobic and negatively charged amino acids and is found exclusively in kidneys, the liver and intestine. The OCT1 transport protein transports cations of varying structure, is inhibited by a large number of cationic substances of differing hydrophobicity and possesses functional properties which differ from those of a previously known polyspecific transport protein (multidrug transporter), which is only able to transport very hydrophobic substances. The transport protein OCT1 is regarded as a new prototype of a polyspecific transport protein in mammals.
Many organic cations, including frequently used pharmaceuticals such as antihistamines, antiarrhythmics, sedatives, opiates, diuretics, cytostatic agents and antibiotics, are excreted into the urine and into the bile by means of being actively transported through kidney epithelial cells and hepatocytes. When being actively secreted in the kidney, the cations are transported by polyspecific transport systems in the basolateral and luminal plasma membranes of the proximal renal tubules. The two systems differ as regards their function. The transport proteins in the basolateral membrane, which are able to transport structurally different cations such as tetraethylammonium (TEA), N'-methylnicotinamide (NMN) and N-methyl-4-phenylpyridinium (MPP), are inhibited by a large number of extracellular cations of differing structure. These transport proteins can be driven by a membrane potential which is internally negative and by the oppositely directed transport of intracellular substrates. Two transport systems have been described in the luminal membrane which, while being driven by an outwardly directed proton gradient, are not affected by the membrane potential. One of these transport systems has a broad substrate specificity which is comparable to that of the cation transport system in the basolateral membrane of proximal renal tubules. Owing to functional similarities, it is assumed that this polyspecific transport system in the luminal membrane is identical to the extraneuronal transport system for noradrenalin in the heart.